Figure 2. Schematic representation of the domains of PLCG1. The protein contains eight domains, four of which are unique to PLCG family. The PLCG 'specific array' of domains, comprising a "split" PH domain flanking two tandem SH2 domains and one SH3 domain, is inserted between the two halves (X and Y) of the TIM-barrel catalytic domain. Several other domains including two PH domains, one C2 domain and one EF hand motifs. The numering of the amino acid residues is for human PLCG1 (Suh et al., 2008; Bunney and Katan, 2011).

PLCG1 localizes predominantly in the plasmatic membrane, cytoplasm and nucleus.

Function

PLCG1 is a protein involved in multiple cellular processes. A potent inhibitor of PLCG1 (U-73122) has been reported to inhibit PLCG1-dependent processes in cells (Smith et al., 1990; Thompson et al., 1991; Thomas et al., 2003; Li et al., 2005). The inhibition of PLCG1 may be an important mechanism for an antiproliferative effect on the human cancer cells. Role in the production of the second messenger molecules: PLCG1 mediates the production of diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (IP3) from the hydrolysis of phosphatidynositol-4,5-bisphosphate (PIP2) (Williams et al., 1996). These second messengers are essential for T cell activation (Lin et al., 2001). Role in cellular proliferation: PLCG1 is associated with tumor development, and it is overexpressed in some tumors (Shin et al., 2007). This overexpression stimulates MMP-3 expression. PLCG1 is required for metastasis development (Sala et al., 2008). Role in angiogenesis: PLCG1 plays an important role in angiogenesis (Husain et al., 2010). PLCG1 is activated by vascular endothelial growth factor receptor-2 (VEGFR-2) in endothelial cells (Singh et al., 2007) and in neoplastic Barrett's cells (Zhang et al., 2013). Role in the regulation of intracellular signaling: PLCG1 plays a role in mediating T-cell activities downstream of TCR activity. PLCG1 can be activated by receptor tyrosine kinases: EGFR (Nishibe et al., 1990; Wu et al., 2009), PDGFR (Larose et al., 1993), FGFR (Peters et al., 1992), NGFR (Middlemas et al., 1994) and HGFR (Davies et al., 2008). PLCG1 is a molecule associate with lipid rafts, it translocates from the cytosol to lipid rafts during TCR signaling (Verí et al., 2001). Role in the mobilization of Ca2+: this process is to activate phosphatase calcineurin, which in turn dephosphorylates and activates NFAT (Rao et al., 1997). Truncation of the N terminus of Vav1 is accompanied by a decrease in PLCG1 phosphorylation and this inhibits calcium mobilization (Knyazhitsky et al., 2012). Role in cytoskeleton: PLCG1 plays a role in actin reorganization (Pei et al., 1996; Wells, 2000; Wang et al., 2007; Li et al., 2009). Role in adhesion and migration: PLCG1 mediates cell adhesion and migration through an undefined mechanism (Wang et al., 2007; Crooke et al., 2009). PLCG1 plays a role in integrin-mediated cell motility processes (Jones et al., 2005). Role in apoptosis: PLCG1 is proteolytically cleaved by group II caspases especially by caspase-3 and caspase-7 during apoptosis. This results in the loss of receptor-mediated tyrosine phosphorylation (Bae et al., 2000). PLCG1 plays a protective role in H2O2-induced PC12 cells death (Yuan et al., 2009). The Fas-mediated apoptosis requires endoplasmic reticulum-mediated calcium release in a mechanism dependent on PLCG1 activation (Wozniak et al., 2006). Role in transformation: PLCG1 interacts with Middle tumor antigen (MT). The tyrosine phosphorylation level of PLCG1 is elevated in cells expressing wild type MT but not in cells expressing Tyr322→Phe MT (Su et al., 1995). Role in autoimmune symptoms: PLCG1 deficiency impairs the development and function regulatory cells (FoxP3+), causing inflammatory/autoimmune symptoms (Fu et al., 2010).

Homology

The protein contains eight domains, four of which are unique to PLCG family (Suh et al., 2008). The PLCG 'specific array' of domains, comprising a "split" PH domain flanking two tandem SH2 domains and one SH3 domain, is inserted between the two halves (X and Y) of the TIM-barrel catalytic domain (Bunney and Katan, 2011). Several other domains including two PH domains, one C2 domain and one EF hand motifs (Suh et al., 2008).

Mutations

Somatic

99 mutations have been described in the PLCG1 gene, according to the Catalogue of Somatic Mutations in Cancer (COSMIC) database. De novo mutation has been described in patients with Cutaneous T-cell lymphoma (CTCL): S345F (10/53 analyzed CTCL samples, 19%) (Vaqué et al., 2014).

Overexpression of PLCG1 is a marker of development of metastases in breast cancer (Lattanzio et al., 2013). Loss of PLCG1 in part mimicked the effect of miR-200b/miR-c/miR-429 overexpression in viability, apoptosis and EGF-driven cell invasion of breast cancer cells (Uhlmann et al., 2010).

PLCG1 has a role in the regulation of PC3LN3 (human prostate carcinoma cells) cell adhesion that appears to be independent of its effects on tumour cell chemotactic migration and spreading in response to extracellular matrix (Peak et al., 2008).